Evidence for a cerebral effect of the hepatitis C virus
This report appears as a Research Letter in Lancet, which is not the same as a peer reviewed study. Nonetheless, the report is creditable to me, and further research attention is needed. This report appears to be a follow-up to poster/abstract these researchers reported at EASL 2000. This was the subject of my report HCV & the Brain. Below is the entire article without the tables. Starting off below is the abstract and a few highlights before the entire article.
Here is the link to the NATAP called HCV & Brain Dysfunction report from EASL 2000 on DM Horton's initial presentation which I viewed: HCV and Brain Dysfunction
Research letters
Lancet 2001; 358: 38-39
Daniel M Forton, Joanna M Allsop,
Janice Main, Graham R Foster, Howard C Thomas, Simon D Taylor-Robinson
--We considered that HCV infection itself may affect cerebral function and looked at cerebral choline/creatine ratios with proton magnetic-resonance spectroscopy (1H MRS) in patients and controls
--30 patients with histologically defined mild chronic HCV infection were randomly selected. Liver biopsies showed mild inflammation only, with no cirrhosis or significant fibrosis (table 1). 1H MRS was also performed in 29 age-matched and sex-matched healthy controls and in 12 patients with chronic hepatitis B. 20 (67%) patients with HCV infection, but no healthy controls or patients with hepatitis B infection, gave ahistory of intravenous drug use (IVDU)
--Patients with significant fibrosis or cirrhosis were excluded from the study so we can conclude that the findings are not due to minimal hepatic encephalopathy.
-- A neuroradiologist reviewed the MR images. the Cho/Cr ratios were significantly higher in the white matter and basal ganglia of the HCV group compared with both the hepatitis B group and healthy volunteers
--There were no statistically significant differences in the ratios between the HCV patients with a history of IVDU and those without. There was also no association between viral genotype or liver biopsy score and the cerebral metabolite ratios.
--In 1H MRS the choline resonance mainly reflects intracerebral phospholipid cell membrane precursor and degradation products and is increased in conditions where there is cellular proliferation, most notably in inflammatory or infective conditions such as multiple sclerosis, or HIV infection.
--Similar metabolite abnormalities in the same spatial distribution to those reported here have been extensively documented in cerebral HIV infection, in patients both with and without neurological symptoms
--Infection of cerebral microglia by HIV, possibly via infected monocytes, and subsequent microglial activation are thought to underlie the MRS changes. There is good evidence to suggest that HCV infects cells of monocytic lineage,5 raising the possibility that HCV too may infect the brain
--There is good evidence to suggest that HCV infects cells of monocytic lineage,5 raising the possibility that HCV too may infect the brain. An alternative explanation for these findings is a centrally mediated effect of peripherally derived cytokines, either via their transfer across the blood-brain barrier or through an interaction with the cerebral vascular endothelium and the generation of secondary messengers. Our preliminary data suggest that there is altered cerebral metabolism in patients with chronic HCV infection which cannot be explained by hepatic encephalopathy or a history of drug use.
ABSTRACT: Patients with hepatitis C virus (HCV) infection frequently complain of symptoms akin to the chronic fatigue syndrome and score worse on health-related quality of life indices than matched controls. We address the hypothesis that HCV itself affects cerebral function. Using proton magnetic-resonance spectroscopy we have shown elevations in basal ganglia and white matter choline/creatine ratios in patients with histologically-mild hepatitis C, compared with healthy volunteers and patients with hepatitis B. This elevation is unrelated to hepatic encephalopathy or a history of intravenous drug abuse, and suggests that a biological process underlies the extrahepatic symptoms in chronic HCV infection.
REPORT: Several studies have shown that patients with chronic hepatitis C virus (HCV) infection score worse than matched controls on health-related quality of life indices and that their scores improve with successful antiviral treatment.1 These findings agree with the clinical observation that such patients frequently complain of fatigue, lassitude, impaired memory ("brain fog") and a perceived inability to function effectively, even in the absence of clinically significant liver disease. It is not known whether social, psychological, or biological factors cause these complaints.
We considered that HCV infection itself may affect cerebral function and looked at cerebral choline/creatine ratios with proton magnetic-resonance spectroscopy (1H MRS) in patients and controls. 30 patients with histologically defined mild chronic HCV infection were randomly selected. Liver biopsies showed mild inflammation only, with no cirrhosis or significant fibrosis (table 1). 1H MRS was also performed in 29 age-matched and sex-matched healthy controls and in 12 patients with chronic hepatitis B. 20 (67%) patients with HCV infection, but no healthy controls or patients with hepatitis B infection, gave ahistory of intravenous drug use (IVDU)
All subjects underwent cerebral MRS, using a 1·5T Eclipse spectroscopy system (Marconi Medical Systems, Cleveland, OH, USA). We used T1-weighted magnetic-resonance (MR) images to exclude organic brain disease and to position the voxels of interest. We positioned three 8 cm3 voxels; in the basal ganglia, in the white matter at the level of the centrum semiovale, and in the occipital grey matter. We then performed single voxel 1H MRS examinations with an automated PRESS sequence (TR/TE 1500/135 ms, 128 acquisitions). MR spectra were analysed by a single blinded observer. Peak areas were measured for choline (Cho), creatine (Cr) and N-acetylaspartate (NAA). Ratios for NAA/Cr and Cho/Cr were calculated and compared with a one-way analysis of variance (ANOVA) with post-hoc comparisons, using contrasts (SPSS version 9).
A neuroradiologist reviewed the MR images. One patient had an arachnoid cyst. There was no evidence of cerebral vasculitis or white-matter abnormalities in any of the patients or controls. The metabolite ratios were normally distributed. There were no differences in the grey matter metabolite ratios between the patients with HCV, healthy controls, and hepatitis B controls. However, the Cho/Cr ratios were significantly higher in the white matter and basal ganglia of the HCV group compared with both the hepatitis B group and healthy volunteers (table 2).
Groups were compared with a one-way ANOVA and between group comparisons performed using post-hoc contrasts with a Bonferroni adjustment for multiple comparisons. p values greater than 1·00 are rounded down to 1·00
A second ANOVA was performed to compare the Cho/Cr ratios in HCV patients with and without a history of IVDU with the control groups. There were no statistically significant differences in the ratios between the HCV patients with a history of IVDU and those without. The mean alanine aminotransferase concentration was higher in the hepatitis B group than in the HCV group (93 vs 47 IU/L respectively, p<0·03), but no association was found between the concentration of alanine aminotransferase and the metabolite ratios in the HCV or hepatitis B group. There was also no association between viral genotype or liver biopsy score and the cerebral metabolite ratios.
These data demonstrate cerebral 1H MRS metabolite abnormalities in patients with histologically defined mild HCV infection. Patients with significant fibrosis or cirrhosis were excluded from the study so we can conclude that the findings are not due to minimal hepatic encephalopathy. Indeed, spectroscopic studies of hepatic encephalopathy show globally reduced Cho/Cr ratios.2 We found no statistically significant differences in 1H MRS between HCV patients with or without a history of IVDU.
A number of cerebral MRS studies have investigated the effect of illicit drug use, but neither chronic use of cocaine or heroin has been found to increase cerebral choline-containing compounds.3 It is therefore unlikely that a history of IVDU underlies the MR abnormalities in the HCV group. In 1H MRS the choline resonance mainly reflects intracerebral phospholipid cell membrane precursor and degradation products and is increased in conditions where there is cellular proliferation, most notably in inflammatory or infective conditions such as multiple sclerosis, or HIV infection.
Similar metabolite abnormalities in the same spatial distribution to those reported here have been extensively documented in cerebral HIV infection, in patients both with and without neurological symptoms.4 Infection of cerebral microglia by HIV, possibly via infected monocytes, and subsequent microglial activation are thought to underlie the MRS changes. There is good evidence to suggest that HCV infects cells of monocytic lineage,5 raising the possibility that HCV too may infect the brain. An alternative explanation for these findings is a centrally mediated effect of peripherally derived cytokines, either via their transfer across the blood-brain barrier or through an interaction with the cerebral vascular endothelium and the generation of secondary messengers. Our preliminary data suggest that there is altered cerebral metabolism in patients with chronic HCV infection which cannot be explained by hepatic encephalopathy or a history of drug use. These findings have implications for the direction of future research and ultimately for patient treatment.
We thank Mark Wright, Peter Karayiannis of the Hepatology section, ICSM and Glyn Coutts, Alison Fletcher, Serena Counsell, and Louise Goff of the Robert Steiner MR Unit, Hammersmith Hospital for their help with this study. We are also thank Professor Graeme Bydder for neuroradiological advice. This work was partly supported by Marconi Medical Systems International (Cleveland, OH, USA) and the Medical Research Council, UK.
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